What is the cause of leukocytosis (elevated white blood cell count) with neutrophilia (elevated neutrophil count) in a 62-year-old male after hospital discharge while on doxycycline (doxycycline hyclate)?

Leukocytosis with Neutrophilia Post-Hospital Discharge on Doxycycline

Most Likely Cause

This patient's leukocytosis (WBC 20.3) with neutrophilia (15.3) most likely represents an ongoing or incompletely treated bacterial infection, given the absolute neutrophil count elevation, presence of immature granulocytes (0.4), and recent hospitalization requiring antibiotic therapy. 1, 2

Systematic Diagnostic Approach

Immediate Assessment for Bacterial Infection

The laboratory values strongly suggest active bacterial infection:

• Absolute neutrophil count of 15.3 K/μL is significantly elevated and carries a likelihood ratio of 3.7 for bacterial infection when WBC >14,000/mm³ 1, 2
• Presence of immature granulocytes (0.4) indicates a "left shift" which has a likelihood ratio of 4.7 for bacterial infection, even when total WBC is only mildly elevated 1, 2
• The neutrophil percentage (approximately 75%) combined with immature forms suggests active bone marrow response to infection 2

Most Common Bacterial Infection Sources to Evaluate

Obtain focused history and examination for these specific infection sites: 1, 2

• Respiratory tract: Persistent cough, dyspnea, chest pain, or incomplete resolution of pneumonia
• Urinary tract: Dysuria, flank pain, costovertebral angle tenderness (particularly important given age and sex)
• Skin/soft tissue: Surgical sites, wounds, cellulitis, or abscess formation
• Gastrointestinal: Abdominal pain, diarrhea (especially Clostridium difficile post-hospitalization)

Critical Diagnostic Tests Within 24 Hours

Order these specific tests immediately: 1, 2

1. Manual differential count (not automated) to calculate absolute band count—if ≥1,500 cells/mm³, this carries the highest likelihood ratio (14.5) for documented bacterial infection 1, 2
2. Blood cultures if fever, chills, or systemic symptoms present 2
3. Urinalysis with culture given age and risk for urinary tract infection 2
4. Chest X-ray if any respiratory symptoms or recent pneumonia 2
5. C-reactive protein or ESR to assess inflammatory burden 1

Alternative Causes to Consider

Persistent Inflammation-Immunosuppression Catabolism Syndrome (PICS)

Recent hospitalization itself can cause prolonged leukocytosis without active infection: 3

• Patients with major trauma, surgery, sepsis, or cerebrovascular events develop persistent leukocytosis (mean WBC 26.4 ± 8.8) lasting 14.5 ± 10.6 days post-hospitalization 3
• This represents tissue damage-driven inflammation (DAMPs) rather than active infection 3
• However, this diagnosis should only be considered after excluding active bacterial infection 3

Medication Effects

Doxycycline itself is an unlikely cause of this leukocytosis: 4

• Doxycycline rarely causes neutropenia, not neutrophilia 4
• If the patient received corticosteroids during hospitalization, this could contribute: high-dose steroids cause mean WBC increase of 4.84 × 10⁹/L within 48 hours 5
• Any WBC increase beyond 4.84 × 10⁹/L after steroids suggests infection rather than medication effect 5

Inadequate Antibiotic Coverage

Doxycycline has limited spectrum and may be inadequate for certain infections: 6

• Doxycycline does not cover common bacterial pneumonia pathogens like Streptococcus pneumoniae or Staphylococcus aureus effectively 6
• If the original infection was not fully treated or was caused by a doxycycline-resistant organism, leukocytosis will persist 6

Critical Pitfalls to Avoid

Do not ignore this leukocytosis as "stress-related" without excluding infection: 1, 2

• The combination of elevated absolute neutrophil count (15.3), immature granulocytes (0.4), and recent hospitalization requiring antibiotics mandates infection workup 1, 2
• Do not rely on automated differential alone—manual differential is essential to assess band forms and calculate absolute band count 1, 7
• Do not assume doxycycline is providing adequate coverage without confirming the original infection source and organism sensitivities 6

Do not delay evaluation if any signs of sepsis develop: 7

• Hypotension <90 mmHg systolic, tachycardia, tachypnea, or altered mental status require immediate broad-spectrum antibiotics within 1 hour 7
• Mortality increases with each hour of delay in septic patients 7

Recommended Management Algorithm

1. Obtain manual differential and calculate absolute band count immediately 1, 2
2. If absolute band count ≥1,500 cells/mm³ or clinical signs of infection present: initiate site-specific cultures and consider broadening antibiotic coverage beyond doxycycline 2, 7
3. If no infection source identified after thorough workup: consider PICS from recent hospitalization, but continue monitoring with serial CBCs every 2-3 days 3
4. If leukocytosis persists beyond 2 weeks without identified cause: refer to hematology to exclude primary bone marrow disorder 1, 8